SCOPE OF ARTICLE

This article is limited to discussion of reactions to insect stings and bites. In most regions, the former dominate and will be the prime topic here. This article does not deal with other allergic reactions to inhaled or ingested insect components or products.

DEFINITIONS

Sensitization to insect venom refers to the presence of specific sensitivity to insect venom, most commonly mediated by IgE and demonstrable by skin testing or in vitro assay.

Allergy to insect venom refers to a clinical reaction to one or more stings that is greater than would be expected in the general population and results from specific sensitization to that venom.

SYMPTOMS AND SIGNS

Most individuals will develop limited local swelling in response to a sting that is of nuisance value. A minority of persons will develop excessive local swelling, which may be either “immediate” (developing and peaking within 1-2 hours) or “delayed” (developing hours after the sting, increasing for 24-48 hours and resolving after 3-10 days). Such events only threaten life if in close proximity to the airway.

A small percentage of the population develops “systemic” or “generalized” reactions that extend beyond areas contiguous with the sting. Most of these are immediate IgE-mediated allergic reactions and show the same range of features as other such reactions. These include cutaneous, mucosal, respiratory, cardiovascular, gastrointestinal and/or neurological involvement (see table 1). Systemic reactions have commonly been classified with the use of the four stage system of Ulrich Mueller, a modification of the system of Harry Mueller. More recently, Simon Brown described a three tier system (table 1) that aimed at describing the significance of features in terms of probability of evolution of hypoxia and/or hypotension. Recently WAO has proposed a classification aimed at standardizing reports of reactions to subcutaneous immunotherapy (Cox, Larenas-Linnemann et al 2010),

Hypotension appears to be more prominent in severe reactions to insect stings than in allergic reactions to foods. This may reflect the tendency of severe sting reactions to involve older subjects. Systemic allergic reactions of rapid onset with lethal potential (e.g. those with respiratory or vascular compromise) constitute “anaphylaxis”. Rarely, stings can cause other unusual manifestations that are more likely to be toxic than hypersensitivity reactions.

EPIDEMIOLOGY AND ETIOLOGY

Estimates of the prevalence of subjects who have experienced immediate systemic reactions to insect stings vary from 1% to 7% of the general population. The insects that account for the problem vary by region. The honey bee is ubiquitous, yellow jackets (Vespula) cause sting allergy problems across diverse temperate climates, paper wasps (Polistes) and in some regions hornets (Vespa) tend to be important at lower latitudes. Stinging ants are more restricted in their distribution, but the imported fire ant (Solenopsis invicta) and jack jumper ant (Myrmecia pilosula spp) dominate clinical sting allergy in areas of South Eastern-South Central USA and South Eastern Australia, respectively, whereas species of Pachycondyla are major public health problems in East Asia and the Arabian Peninsula.

Recently, anaphylaxis to the bite of the paralysis tick, Ixodes holocyclus, has been recognized as an important problem on the east coast of Australia and is associated in many subjects with subsequent anaphylaxis to red meat. There have also been many reports of anaphylaxis to tick bites in Europe and it has been demonstrated that bites from Ixodes (Australia, Europe), Amblyomma and Dermacentor spp (North America) are important stimuli in sensitization to the carbohydrate allergen, galactose alpha-1,3- galactose which is widespread in non- primate animals and has been linked also to allergic reactions to the monoclonal antibody cetuximab. Anaphylaxis to biting insects like kissing bug (Triatoma), horseflies (Tabanus spp), mosquitoes (Aedes, Culex, Anopheles) has rarely been reported.

Estimates of the number of deaths from sting anaphylaxis are likely to be an underestimate and to vary widely regionally. It is most likely in the range 1-10 per 10 million per annum based on estimates in the USA and Australia.

REFERRAL AND DIAGNOSIS

Accurate diagnosis is essential because it has long-term consequences, including provision of an epinephrine/adrenaline auto-injector, long-term venom immunotherapy and, in some cases, change in occupation or relocation. It requires knowledge of the entomology of the region, of the natural history of the sting allergy (see below) and of the availability and limitations of the skin and in vitro tests for venom allergy. Referral to an experienced allergy specialist is strongly recommended.

Diagnosis must be made at several levels:

The nature of the subject’s worst insect sting reaction. An accurate history of the worst sting reaction is essential because it is important in predicting future risk (see the section “Natural History and Risk Assessment” below). Clinical responses to stings are variable events, and the clinician should be guided by the subject’s worst reaction to the insect. If possible, case records should be reviewed for objective manifestations, but it must be borne in mind that some subjects may have been more severely compromised before reaching medical care.

The probable identity of the responsible insect. Features to consider when identifying the insect include observations made at the time of the sting, the place and circumstances of the sting (e.g. proximity of garbage or food favors the yellow jacket, native bushland in South East Australia favors the jack jumper ant), the presence or absence of a stinger in the skin (the presence favors the honey bee, Apis mellifera or among vespids, Vespula maculifrons), past sting history and any culprit specimen presented. Most sting reactions occur in the warmer months. Knowledge of regional variation in seasonal species can be helpful in identifying the most likely culprit. Vigorous exercise or hot showers and recurrent stings in the same season also appear to be risk factors for anaphylaxis.

Skin test or in vitro evidence of IgE sensitization of the subject to relevant venoms. Specialist expertise is required because of the limitations in availability and sensitivity of both skin and in vitro tests for venom-specific IgE. Testing should be carried out with venoms of all likely insects. Sensitivity of venom skin testing (VST) and in vitro specific IgE (sIgE) varies greatly across studies but at best is 90-95% for VST and around 90% (HBV) or 80-90% (YJ) for in vitro sIgE with a significant proportion of subjects negative in one test positive in the other. Nevertheless, in several large studies, approximately 1 in 3 patients with a convincing history of systemic reaction to a sting had negative VST. Even with negative venom skin testing and in vitro serum IgE tests, a repeat skin test 1-3 months later should be negative before it is concluded that the subject lacks demonstrable specific IgE to the venom. VST necessitates satisfactory positive and negative controls and a positive response to intradermal testing at 1 microgram/ml or less. Such testing can rarely precipitate a systemic allergic reaction, however, and expertise and facilities for resuscitation should be immediately available.

Other in vitro tests. Mast cell tryptase levels measured within 30 minutes to 8 hours after the onset of the index reaction may, if raised, support the conclusion that the reaction features resulted from an allergic reaction; however, a negative test result does not exclude that possibility. Comparison of the acute with a convalescent specimen may increase sensitivity (a 35% increase from baseline is considered significant). If baseline mast cell tryptase is raised, the subject may have a systemic mast cell disorder (see the section “Management of co-morbidities” below). In vitro tests measuring activation of surface markers of basophils or release of mediators from these cells after addition of the allergen may be helpful in individual patients with a strong history of sting anaphylaxis but negative skin tests and no detectable serum IgE to venoms or with apparent double sensitization. Such assays require standardization before they can be considered in routine practice..
Specific IgE testing to recombinant venom allergens offers increased specificity, valuable in cases with apparent dual sensitization and in some studies increased sensitivity but optimal combinations are yet to be defined.

Sting challenges. These are the gold standard for clinical sensitivity in research, but have a limited place in clinical practice because of substantial risks of anaphylaxis and of either false-negative responses or sensitization to future stings, especially if performed in untreated patients. They should only be undertaken when there is a strong indication for the procedure, high-level facilities and expertise, informed consent and institutional ethics committee approval. In most European countries sting challenges are only performed for the confirmation of efficacy during venom immunotherapy.

NATURAL HISTORY AND RISK ASSESSMENT

Humility is appropriate in approaching this topic for two reasons: first, almost half of subjects who die of apparent allergic reactions to stings have no known history of an earlier systemic reaction and second, sensitization to insect venoms is much more common than is clinical allergy to the same insect venoms. Further, any prediction of risk based on published studies cannot be extrapolated with confidence to a specific patient. Nevertheless, from epidemiological and deliberate sting study outcomes, the following strong trends are apparent:

Subjects who have experienced only enhanced local or even generalized cutaneous reactions run a relatively low risk, of the order of 5-20%, of a systemic reaction, which is usually of limited severity, to a subsequent sting by an insect of the same species.

A previous severe systemic reaction and, in particular, hypotensive anaphylaxis indicates a high risk (50-70%) of a further severe reaction.

Risk of a severe or lethal reaction appears to rise with increasing age and possibly cardio-respiratory co-morbidities although these factors are difficult to separate. There is conflicting opinion about whether the risk of developing anaphylaxis is increased by cardiovascular medications such as beta blockers, ACEI or combinations of the two but failure to demonstrate such effect in some recent large studies suggests that any increased risk is limited and must be viewed in the context of the well-established cardio-vascular benefits of these medications. However whether these agents increase the severity or impede treatment of anaphylaxis, act differently in patients on VIT or untreated patients and whether such effects can be extricated from the effects of co-morbidities remain unresolved.

In deliberate sting studies, higher proportions of subjects who have had recent systemic allergic reactions to jack jumper ant or honey bee stings have had a similar reaction to their next sting compared with yellow jacket-allergic subjects (respective figures are approximately 70-76 %, 52-75% and 25-40%). Such outcomes will vary with the age of subject; the severity of the index sting reaction, venom delivery in the sting challenge and possibly the time elapsed since the last sting.

Positive tests for IgE to venom increase the risk of a systemic reaction to a sting, and even asymptomatic, sensitized subjects carry a significant but low risk (circa 10-15%). However, except for allergy to jack jumper ant venom, the degree of skin test reactivity appears to be a poor predictor of reaction severity.

Factors that appear common in forensic cases are remote rural occupations or recreation, cardiorespiratory co-morbidities and not necessarily as an independent risk, treatments for vascular disease.

MANAGEMENT

Acute treatment

The reader is directed to the Updated Practice Parameter on management of anaphylaxis (2010) and World Allergy Organisation anaphylaxis guidelines: Summary (2011) [http://www.jacionline.org/article/S0091-6749(11)00128-X/pdf] for a review of anaphylaxis and its management. . The importance and use of epinephrine is reviewed in the previous references and in Simons and Simons, 2010. Epinephrine is the key medication in managing anaphylaxis. Although there is strong evidence for the efficacy (and in expert hands, safety) of epinephrine infusion from a large prospective study of reactions to deliberate jumper ant stings, the simple procedure of injecting appropriate doses of epinephrine IM into the anterior thigh is recommended for prompt initiation of effective therapy with a high margin of safety. Administration of high-flow oxygen and airway support and in hypotensive subjects a horizontal, legs-elevated posture and rapid infusions of isotonic saline through a large-bore cannula are recommended. For life-threatening reactions, emergency support should be summoned because further measures might be required that necessitate special expertise (e.g. intubation, tracheostomy or use of selective vasopressor medications). There appears to be no reliable way of predicting biphasic anaphylaxis or its timing. Participants in the second NIAID/FAAN symposium on anaphylaxis recommended that observation times be individualized on the basis of the severity of the initial reaction, reliability of the patient and access to care. Observation for 3-6 hours, depending on reaction severity, is likely to capture most delayed reactions but uncommonly a reaction may occur beyond 6 hours after the onset of the original reaction.

Emergency plans and epinephrine auto-injectors

Subjects with a history of an immediate systemic reaction to a sting need a written plan that includes the following: symptom recognition, guidelines for summoning assistance, indications for and method of use of automated epinephrine/adrenaline syringe and indication that urgent transport to emergency care and at least 3-6 hours of observation at the point of care after symptom resolution are required. Such plans must take account of regional factors and past reactions, including speed of evolution and severity. Prospective sting studies suggest that some adults require provision of and guidelines for use of a second automated epinephrine syringe, depending on anticipated reaction severity and distance from care. Published data indicate that compliance with carriage, maintenance and use of automated epinephrine syringes is often disappointing, which underscores the need for careful instruction, periodic retraining and emphasis that other medications do not represent alternatives to the use of epinephrine except for the mildest of systemic reactions (e.g. slowly evolving reactions confined to the skin). However, small doses of epinephrine are not contraindicated in these cases.

Ticks should not be removed from tick allergic subjects until emergency care has been reached as this often stimulates the tick to introduce more saliva into the subject. The tick should be killed in situ and ether spray (available for automotive use or to freeze warts) appears to be very effective.

Management of co-morbidities

It appears probable that cardiovascular and respiratory co-morbidities contribute to the risks of an adverse outcome. Treatment of such conditions should be optimized in consultation with other health care professionals. As discussed under “natural history and risk assessment, section 3”, a particularly difficult issue arises when a subject has indications for medications such as beta blocking drugs or ACE inhibitors that may potentiate anaphylaxis or complicate its management. A team approach is required that weighs the relative risks of each condition and the risks and benefits of each medication. There may be greater risk in discontinuing or withholding these medications than in permitting them.

Identification of subjects with raised baseline mast cell tryptase is important because such subjects are disproportionately at risk of severe reactions to insect stings and may be reactive to other stimuli. Please refer to following section on venom immunotherapy.

Venom immunotherapy

Insect VIT is a potent tool for preventing sting anaphylaxis. Controlled studies demonstrate that immunotherapy with vespid, honey bee and jack jumper ant venoms are highly effective. Once subjects are receiving maintenance doses of yellow jacket or jumper ant venom, the risk of an immediate generalized reaction to a sting is approximately 5% per sting, and these reactions are almost always less severe than the previous sting reactions. Honey bee VIT is less effective by that criterion (the risk of a generalized reaction is of the order of 20% per sting), but needs to be assessed against an adverse natural history without immunotherapy. Many of the documented “failures” have involved mild systemic reactions.

Although a statistical assessment of the effect of VIT on the risk of death is difficult if not impossible, efforts to make such estimates have concluded that the cost of saving a single life is in the millions of dollars. However, studies in yellow jacket-sensitive subjects have consistently shown a marked improvement in quality of life with VIT but not necessarily with prescription of epinephrine auto-injectors. This has been shown even in dermal reactors. Further, cognitive impairment after severe sting reactions is an uncommon but poorly quantitated outcome.

Problems with VIT include the following:

Selection of subjects and co-morbidities. Any subject with a history of a systemic allergic reaction to a sting and evidence by skin testing or in vitro tests of specific IgE to that venom should be considered for VIT. There is not yet evidence to support the use of VIT in asymptomatic sensitized subjects or in subjects who have experienced systemic reactions but lack evidence of IgE to the venom. There is recent evidence that VIT can reduce the tendency to excessively large local reactions, but given costs and morbidity, use of VIT for this purpose should be highly selective for those who have frequent and unavoidable reactions that cause great morbidity and time lost from work, and usually require treatment with corticosteroids. Subjects whose co-morbidities or treatments might render them at high risk of adverse VIT outcomes may be the subjects most at risk when left untreated and special considerations beyond the scope of this general review apply to this group. Elevated baseline serum tryptase or definite systemic mastocytosis are associated with an increased risk of side effects during venom immunotherapy, of systemic sting reactions during VIT, and of relapses after stopping it. Four fatal sting reactions have been reported after stopping venom immunotherapy. Three occurred in patients with documented systemic mastocytosis, in the fourth mastocytosis, was not considered in the differential diagnosis. For this reason, VIT in patients with systemic mastocytosis is recommended for life. Recent studies have highlighted that systemic mastocytosis or mast cell activation syndrome needs to be considered in any subject with history of systemic reaction to hymenoptera sting with baseline mast cell tryptase above 11.4 ng/ml, that absence of skin features is common and that systemic reactions to vespid stings, hypotensive anaphylaxis and negative tests for venom allergy despite history of anaphylaxis to hymenoptera sting should heighten consideration of need to investigate for systemic mast cell disorder. This group of subjects presenting with sting anaphylaxis appear, apart from the sting reactivity, to have relatively benign monoclonal mast cell disorders, at least at this stage of follow up.

Regimens. The most rigorous trials have used regimens in which incremental doses are given in ambulatory care at approximately weekly visits, either several doses per visit (“clustered”) or single doses per visit or a mixture of the two. Standard (traditional) regimens achieve the maintenance dose in months, “semi-rush” in weeks, “rush” in 2-3 days, and “ultra-rush” in hours. Rush and ultra-rush regimens are generally performed in a hospital setting. Such regimens are now widely used because they appear to offer greater convenience and accelerated achievement of the target maintenance dose. With VIT to yellow jacket, such regimens appear also to have safety advantages, but whether this pertains to other venoms, some of which engender higher reaction rates during VIT, is uncertain. Rush regimens can have both advantages (more rapid protection, fewer clinic visits) and possibly disadvantages (increased risk of systemic reactions in two large studies). Similarly, the selection of monthly 100-microgram maintenance doses for vespid, honey bee and jack jumper ant VIT has been empirical. Some subjects benefit from doses as low as 50 mcg, whilst others require doses of 250 mcg. Twelve week intervals have proven safe and effective for many patients after several years of VIT at intervals gradually increasing from 4 to 8 weeks but there is a paucity of data to establish the efficacy of a 12 week interval in the first 1-2 years of VIT.

Morbidity. Within published trials and large-scale prospectively defined studies, 10-40% of subjects have experienced systemic allergic reactions to VIT. Within that range, yellow jacket venom gives fewer reactions than does bee or jumper ant VIT. Whilst most reactions fall short of anaphylaxis and there are reports that VIT is as safe (or risky) as aeroallergen immunotherapy, treating patients with a history of anaphylaxis should be supervised by professionals who are expert in the recognition and management of anaphylaxis and in the adjustment of treatment protocols for individual patients, VIT requires fully informed consent.

Duration. Suggested endpoints to VIT include reversion of venom skin tests and in vitro tests for venom-specific IgE to negative and/or 5 years of well-tolerated maintenance VIT. However, the first is achieved within 5 years in only a minority of subjects. Furthermore, once immunotherapy ceases, there is a risk of relapse of sting allergy that has been estimated at around 10% per sting. After two decades, the reactivity of the post-VIT population approximates that of sting-allergic subjects who have not had further venom exposure, but sting reactions that do occur post-VIT are generally much milder than pre-VIT sting reactions and there is likely a bias in that those presenting with more severe reactions are more likely to have been given VIT. Patients who are stung frequently or had a history of very severe sting reactions are at somewhat greater risk for sting anaphylaxis after stopping VIT. Approaches to this problem include continuing VIT indefinitely in high-risk subjects, those at risk of frequent stings and ongoing carriage of an epinephrine auto-injector.

Development of VIT. Measures that would facilitate VIT or reduce its morbidity would be valued. Oral antihistamines reduce the frequency of large local and mild systemic reactions to VIT, and may increase the efficacy of treatment. Leukotriene antagonists have been reported to reduce the size and duration of large local reactions to VIT. There are reports of use of IL-10 or of alum adjuvant for this purpose and a few case reports in which omalizumab was used in difficult cases to facilitate VIT when maintenance doses could not be achieved due to severe reactions. The broader applicability and cost-effectiveness of these approaches needs to be studied. Purified (dialysed) venoms and alum (retard) extracts have been shown to reduce local adverse reactions to VIT and may reduce generalized reactions.
In contrast with the experience with vespids, honey bees and jack jumper ants, uncontrolled studies show that whole-body extracts of imported fire ant may be effective, presumably because they contain sufficient venom allergens. Nevertheless, a rigorous comparison with a venom extract appears warranted.
There are cost problems with provision of venoms for some Hymenoptera species, either because of limited distribution (e.g. jack jumper ants (Australia), some paper wasp species, Pachycondlya spp (east Asia and United Arab Emirates) or very small quantities of venom available from each insect (e.g. imported fire ant). There is no commercially available venom for diagnosis or immunotherapy of bumble bee allergy. Experimental work is underway with recombinant allergens for diagnosis and therapy.

PREVENTION

At an individual level, reasonable measures include minimization of situations that attract the responsible insects (e.g. garbage, uneaten food for yellow jackets and perfumes for honey bees) and use of protective footwear and clothing. Of particular importance is the avoidance of drinking from beverage containers or straws because of the high risk of a sting in the oro-pharynx. At a community level, many of the sting allergy problems have an ecological basis, such as introduction of the imported fire ant into the USA where natural controls are lacking and decline of native predators (echidnas) of the jack jumper ant and intrusion of housing into the ants’ natural habitat. The rise in anaphylaxis to Ixodes bites on east coast Australia appears to coincide with success of measures to minimise introduced predators of small marsupials, natural hosts for the ticks.